This pilot proposal, designed to address one of the important research priorities highlighted in the PA- 06-303, is to provide experimental evidence to determine if metabolic syndrome (MS) serves as a possible etiological factor for pancreatic cancer. Pancreatic cancer is the 4th leading cause of cancer death in the United States, and is one of the deadliest cancer types, with the similar incidence and mortality rates. Thus the only effective regimen to reduce pancreatic cancer risk and mortality is via early prevention. Effective prevention of pancreatic cancer requires target on defined etiological factors. However, the pancreatic cancer etiology has not been well understood. MS, which is initially described as a cluster of risk factors that accelerates the onset of cardiovascular disease and type 2 diabetes, is characterized by visceral or intra- abdominal obesity, glucose intolerance, hypertension, low serum HDL-C and high serum triglycerides. Epidemiological investigations have suggested that obesity and diabetes are associated with increased risk of pancreatic cancer. However, limited experimental evidence is available to support if MS is an etiological factor for pancreatic cancer. With increasing prevalence of MS and in parallel increasing pancreatic cancer risk and mortality, there is an urgent need to provide definitive experimental evidence to demonstrate if MS is an etiological factor. Our long-term goal is to test the hypotheses that MS is an etiological risk factor for pancreatic cancer, and effective prevention of pancreatic cancer can be achieved in part by targeting MS. This pilot developmental proposal is designed: (1) to determine if MS induction stimulates pancreatic cancer development, (2) to determine if tea contains active ingredients to prevent pancreatic cancer development in part by alleviating MS. Specific Aim 1 is to determine the effects of the high fat/high simple sugar (HF/HS)-induced MS on pancreatic cancer development in a transgenic mouse model. By using the transgenic pancreatic cancer mouse model, the KRAS (G12D), we will determine if induction of MS by the HF/HS diet will stimulate formation of pancreatic intraepithelial neoplasia (PanIN), and which adipokines and growth factors will be modulated. We expect that the MS will stimulate the formation and progression of PanIN, especially high grade PanIN, associated with modulation of certain adipokines and growth factors. Specific Aim 2 is to evaluate the effects of dietary tea components on inhibiting PanIN formation and progression in mice treated with normal or HF/HS diets. It is expected that the proposed pilot studies will provide experimental evidence to support or against if MS is an etiological factor for pancreatic cancer development. The results will also provide crucial experimental evidence for a future R01 grant application to further investigate effective dietary/nutritional regimens for pancreatic cancer prevention by preventing the development of MS and/or reversing metabolic abnormalities. PUBLIC HEALTH RELEVANCE: The goals of the proposed project are to determine if metabolic syndrome is an etiological factor for pancreatic cancer progression, and to determine if tea bioactive components inhibit pancreatic cancer progression in part by improving metabolic profiles and reversing metabolic abnormalities.